Triglyceride-rich Lipoprotein Particle Research Articles

Peripheral Serotonin Controls Dietary Fat Absorption and Chylomicron Secretion via 5-HT4 Receptor in Males.

Postprandial dyslipidemia is commonly present in people with type 2 diabetes and obesity and is characterized by overproduction of apolipoprotein B48-containing chylomicron particles from the intestine. Peripheral serotonin is emerging as a regulator of energy homeostasis with profound implications for obesity; however, its role in dietary fat absorption and chylomicron production is unknown. Chylomicron production was assessed in Syrian golden hamsters by administering an olive oil gavage and IP poloxamer to inhibit lipoprotein clearance. Administration of serotonin or selective serotonin reuptake inhibitor, fluoxetine, increased postprandial plasma triglyceride (TG) and TG-rich lipoproteins. Conversely, inhibiting serotonin synthesis pharmacologically by p-chlorophenylalanine (PCPA) led to a reduction in both the size and number of TG-rich lipoprotein particles, resulting in lower plasma TG and apolipoprotein B48 levels. The effects of PCPA occurred independently of gastric emptying and vagal afferent signaling. Inhibiting serotonin synthesis by PCPA led to increased TG within the intestinal lumen and elevated levels of TG and cholesterol in the stool when exposed to a high-fat/high-cholesterol diet. These findings imply compromised fat absorption, as evidenced by reduced lipase activity in the duodenum and lower levels of serum bile acids, which are indicative of intestinal bile acids. During the postprandial state, mRNA levels for serotonin receptors (5-HTRs) were upregulated in the proximal intestine. Administration of cisapride, a 5-HT4 receptor agonist, alleviated reductions in postprandial lipemia caused by serotonin synthesis inhibition, indicating that serotonin controls dietary fat absorption and chylomicron secretion via 5-HT4 receptor.

Triglyceride-rich lipoprotein, remnant cholesterol, and apolipoproteins CII, CIII, and E in patients with schizophrenia

Patients with schizophrenia show a disproportionally increased risk of cardiovascular disease. Hypertriglyceridemia is prevalent in this population; however, how this relates to levels of remnant cholesterol, triglyceride (TG)-rich lipoprotein (TRL) particle size and composition, TG turnover, and apolipoprotein (apo) and angiopoietin-like protein (ANGPTL) concentrations is unknown. Fasting levels of cholesterol (total [TC], LDL-C, HDL-C, non-HDL-C and remnant cholesterol) and TG were determined in 110 patients diagnosed with schizophrenia, and 46 healthy controls. TRL particle size, concentration and composition, and β-hydroxybutyrate (TG turnover marker) were assessed by NMR. Levels of apoCII, apoCIII, apoE, ANGPTL3, ANGPTL4, and ANGPTL8 were measured by ELISA, and apoCII, apoCIII and apoE were further evaluated in HDL and non-HDL fractions. Patients with schizophrenia had significantly elevated TG, TG:apoB ratio, non-HDL-C, remnant cholesterol, non-HDL-apoCII and non-HDL-apoCIII, and HDL-apoE (all P < 0.05), lower HDL-C and apoA-I (all P < 0.001), and comparable apoB, TC, TC:apoB ratio, LDL-C, β-hydroxybutyrate, ANGPTL3, ANGPTL4 and ANGPTL8 to healthy controls. Patients had a 12.0- and 2.5-fold increase in the concentration of large and medium TRL particles respectively, but similar cholesterol:TG ratio within each particle. Plasma TG, remnant cholesterol, and large and medium TRL particle concentrations correlated strongly with apoCII, apoCIII, and apoE in the non-HDL fraction, and with apoCIII and apoE in the HDL fraction in patients with schizophrenia. Differences in TG, HDL-C, TRL particle concentrations, apoCIII, and apoE persisted after adjustment for conventional risk factors. These results are consistent with impaired TRL lipolysis and clearance in patients with schizophrenia which may be responsive to targeting apoCIII.

Prediction and verification of the prognostic biomarker SLC2A2 and its association with immune infiltration in gastric cancer.

Gastric cancer (GC) is the fifth most common cause of cancer-associated deaths; however, its treatment options are limited. Despite clinical improvements, chemotherapy resistance and metastasis are major challenges in improving the prognosis and quality of life of patients with GC. Therefore, effective prognostic biomarkers and targets associated with immunological interventions need to be identified. Solute carrier family 2 member 2 (SLC2A2) may serve a role in tumor development and invasion. The present study aimed to evaluate SLC2A2 as a prospective prognostic marker and chemotherapeutic target for GC. SLC2A2 expression in several types of cancer and GC was analyzed using online databases, and the effects of SLC2A2 expression on survival prognosis in GC were investigated. Clinicopathological parameters were examined to explore the association between SLC2A2 expression and overall survival (OS). Associations between SLC2A2 expression and immune infiltration, immune checkpoints and IC50 were estimated using quantification of the tumor immune contexture from human RNA-seq data, the Tumor Immune Estimation Resource 2.0 database and the Genomics of Drug Sensitivity in Cancer database. Differential SLC2A2 expression and the predictive value were validated using the Human Protein Atlas, Gene Expression Omnibus, immunohistochemistry and reverse transcription-quantitative PCR. SLC2A2 expression was downregulated in most types of tumor but upregulated in GC. Functional enrichment analysis revealed an association between SLC2A2 expression and lipid metabolism and the tumor immune microenvironment. According to Gene Ontology term functional enrichment analysis, SLC2A2-related differentially expressed genes were enriched predominantly in 'chylomicron assembly', 'plasma lipoprotein particle assembly', 'high-density lipoprotein particle', 'chylomicron', 'triglyceride-rich plasma lipoprotein particle', 'very-low-density lipoprotein particle'. 'intermembrane lipid transfer activity', 'lipoprotein particle receptor binding', 'cholesterol transporter activity' and 'intermembrane cholesterol transfer activity'. In addition, 'cholesterol metabolism', and 'fat digestion and absorption' were significantly enriched in the Kyoto Encyclopedia of Genes and Genomes pathway analysis. Patients with GC with high SLC2A2 expression had higher levels of neutrophil and M2 macrophage infiltration and a significant inverse correlation was observed between SLC2A2 expression and MYC targets, tumor mutation burden, microsatellite instability and immune checkpoints. Furthermore, patients with high SLC2A2 expression had worse prognosis, including OS, disease-specific survival and progression-free interval. Multivariate regression analysis demonstrated that SLC2A2 could independently prognosticate GC and the nomogram model showed favorable performance for survival prediction. SLC2A2 may be a prospective prognostic marker for GC. The prediction model may improve the prognosis of patients with GC in clinical practice, and SLC2A2 may serve as a novel therapeutic target to provide immunotherapy plans for GC.

Lipidomics of triglyceride-rich lipoproteins derived from hyperlipidemic patients on inflammation.

Triglyceride-rich lipoproteins (TRLs) can have an important role in atherosclerosis development due to their size and ability to penetrate the endothelium. While high plasma triglyceride (TG) levels and chronic inflammation are relevant in metabolic diseases, it remains unclear whether TGs are atherogenic or which TRL-TG-derived metabolites are responsible for inflammation. Here, we aimed to study the lipidome modifications of TRL particles enriched in TG in patients with hyperlipidemia and their associations with a proinflammatory status both invivo and invitro. Using proton nuclear magnetic resonance (1 H-NMR), we analysed the plasma levels of glycoprotein acetyls and the TRL lipidomic profile of 307 patients with dyslipidemia. THP-1-derived macrophages were used as an invitro model to explore the molecular inflammatory effects mediated by TRL. In vivo, higher TRL-TG levels were associated with higher circulating levels of NMR-measured glycoproteins (Glyc-A, Glyc-B and Glyc-F; p < .001). Lipidomic analysis showed that TRL-TG enrichment led to decreased cholesterol and phospholipid content (p < .01), an increase in omega-9, and a decrease in saturated fatty acids (p < .001). THP-1 macrophages exposed to increasing TRL particle concentrations augmented the secretion of IL-1β and TNF-α, which varied based on particle composition. Particles with higher cholesterol and phospholipid contents exerted higher cytokine secretion. The activation of MAPK, Akt/NFκB, and caspase-1 was concurrent with this proinflammatory response. High TRL-TG levels are associated with a higher systemic inflammatory status and increased particle concentrations. Invitro, higher particle numbers increase proinflammatory cytokine secretion, with cholesterol and phospholipid-rich TRL being more proinflammatory.

Interaction of energy and sulfur microbial diet and smoking status with polygenic variants associated with lipoprotein metabolism.

Hypo-high-density lipoprotein cholesterolemia (hypo-HDL-C) contributes to the development of cardiovascular diseases. The hypothesis that the polygenic variants associated with hypo-HDL-C interact with lifestyle factors was examined in 58,701 middle-aged Korean adults who participated in the Korean Genome and Epidemiology Study (KoGES). Participants were categorized into the Low-HDL (case; n = 16,980) and Normal-HDL (n = 41,721) groups. The participants in the Low-HDL group were selected using the guideline-based cutoffs for hypo-HDL-C (<40 mg/dL for men and < 50 mg/dL for women) and included those taking medication for dyslipidemia. The genes associated with hypo-HDL-C were determined through a genome-wide association study (GWAS) in a city hospital-based cohort, and the results were validated in the Ansan/Anung study. The genetic variants for the single nucleotide polymorphism (SNP)-SNP interaction were selected using a generalized multifactor dimensionality reduction analysis, and the polygenic risk score (PRS) generated was evaluated for interaction with lifestyle parameters. The participants with hypo-HDL-C showed a 1.45 and 1.36-fold higher association with myocardial infarction and stroke, respectively. The High-PRS with four SNPs, namely ZPR1_rs3741297, CETP_rs708272, BUD13_rs180327, and ALDH1A2_rs588136, and that with the 11q23.3 haplotype were positively associated with hypo-HDL-C by about 3 times, which was a 2.4-fold higher association than the PRS of 24 SNP with p < 5×10-8. The risk alleles of CETP_rs708272 and ALDH1A2_rs588136 were linked to increased expression in the heart and decreased in the brain, respectively. The selected SNPs were linked to the reverse cholesterol transport pathway, triglyceride-rich lipoprotein particle remodeling pathway, cholesterol storage, and macrophage-derived foam cell differentiation regulation. The PRS of the 4-SNP model interacted with energy intake and smoking status, while that of the haplotype interacted with a glycemic index of the diet, sulfur microbial diet, and smoking status. Adults with a genetic risk for hypo-HDL-C need to modulate their diet and smoking status to reduce their risk.

Mediating role of atherogenic lipoproteins in the relationship between liver fat and coronary artery calcification

Non-alcoholic fatty liver disease (NAFLD) is associated with increased secretion of apoB-containing lipoproteins and increased risk of coronary heart disease (CHD). ApoB-containing lipoproteins include low-density lipoproteins (LDLs) and triglyceride-rich lipoproteins (TRLs); and since both LDLs and TRLs are causally related to CHD, they may mediate a portion of the increased risk of atherosclerosis seen in people with NAFLD. In a cohort of 4161 middle aged men and women, we performed mediation analysis in order to quantify the mediating effect of apoB-containing lipoproteins in the relationship between liver fat and atherosclerosis—as measured by coronary artery calcium score (CACS). We found plasma apoB to mediate 17.6% (95% CI 11–24) of the association between liver fat and CACS. Plasma triglycerides and TRL-cholesterol (both proximate measures of TRL particles) mediated 22.3% (95% CI 11–34) and 21.6% (95% CI 10–33) of the association respectively; whereas LDL-cholesterol mediated 5.4% (95% CI 2.0–9.4). In multivariable models, the mediating effect of TRL-cholesterol and plasma triglycerides showed, again, a higher degree of mediation than LDL-cholesterol, corroborating the results seen in the univariable models. In summary, we find around 20% of the association between liver fat and CACS to be mediated by apoB-containing lipoproteins. In addition, we find that TRLs mediate the majority of this effect whereas LDLs mediate a smaller effect. These results explain part of the observed CAD-risk burden for people with NAFLD and further suggest that TRL-lowering may be particularly beneficial to mitigate NAFLD-associated coronary artery disease risk.

Proteomic-based identification of APCS as candidate protein for diagnosis of patients exhibiting anti-tubercular drug induced liver injury

Traditional markers evaluate anti-tubercular drug-induced liver injury (AT-DILI). However, these markers have certain limitations and studies are in progress to characterize AT-DILI at an early stage. In the present study, 40 patients were categorized and equally distributed into healthy controls, newly diagnosed tuberculosis (TB), TB without hepatotoxicity and TB with hepatotoxicity groups based on their conventional liver function tests. Relative protein quantification was performed on depleted pooled serum samples of each representative group by LC–MS/MS, and validation of shortlisted protein was done by ELISA. Levels of all analysed biochemical parameters showed a statistical increment in the hepatotoxicity group compared to the other three groups, representing AT-DILI. Comparative proteomic analysis between TB with hepatotoxicity versus TB without hepatotoxicity groups highlighted 24 significant differentially expressed proteins, including PROS1, KNG1, CFH, LCAT, APCS and ADIPOQ. Identified proteins were involved in complement activation, triglyceride-rich lipoprotein particle remodelling and pathways comprising complement, coagulation cascades and cholesterol metabolism. Based on functional relevance, the serum amyloid P component (APCS) was shortlisted for validation, and it showed a similar trend as observed in the discovery phase with 100% sensitivity and 87% specificity; however, findings need exploration in larger cohorts.

The association between triglyceride-rich lipoproteins, circulating leukocytes, and low-grade inflammation: The Brazilian Longitudinal Study of Adult Health (ELSA-Brasil)

Experimental studies have linked triglyceride-rich lipoproteins (TRLs) to inflammation, but the extent of this phenomenon in vivo has not been completely elucidated. We investigated the association between TRL subparticles and inflammatory markers (circulating leukocytes, plasma high-sensitivity C-reactive protein [hs-CRP], and GlycA) in the general population. This was a cross-sectional analysis of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). TRLs (number of particles per unit volume) and GlycA were measured by nuclear magnetic resonance spectroscopy. The association between TRLs and inflammatory markers was determined by multiple linear regression models adjusted for demographic data, metabolic conditions, and lifestyle factors. Standardized regression coefficients (beta) with 95% confidence intervals are reported. The study population comprised 4,001 individuals (54% females, age 50±9 years). TRLs, especially medium and large subparticles, were associated with GlycA (beta 0.202 [0.168, 0.235], p<0.001 for total TRLs). There was no association between TRLs and hs-CRP (beta 0.022 [-0.011, 0.056], p=0.190). Medium, large, and very large TRLs were associated with leukocytes, with stronger connections with neutrophils and lymphocytes than monocytes. When TRL subclasses were analyzed as the proportion of the total pool of TRL particles, medium and large TRLs were positively related to leukocytes and GlycA, whereas smaller particles were inversely associated. There are different patterns of association between TRL subparticles and inflammatory markers. The findings support the hypothesis that TRLs (especially medium and larger subparticles) may induce a low-grade inflammatory environment that involves leukocyte activation and is captured by GlycA, but not hs-CRP.

Abstract 12864: Nuclear Magnetic Resonance Lipoprotein Particle Subclasses Associate With Chronic Inflammatory Related Diseases Differently Than Cardiovascular Diseases: The Multi-Ethnic Study of Atherosclerosis

Introduction: Chronic inflammatory related disease (ChrIRD) is a novel outcome capturing non-cancer, non-cardiovascular clinical events driven by subclinical inflammation. Derangements in triglyceride-rich, low-density, and high-density lipoprotein particle (TRLp, LDLp, HDLp) subclass concentrations known to associate with inflammation and future cardiovascular disease have not been extensively evaluated in ChrIRD. Hypothesis: Lipoprotein particle subclasses may predict future ChrIRD in a similar direction and magnitude as with CVD. Methods: We measured 17 lipoprotein subclass particle concentrations by NMR spectroscopy in the Multi-Ethnic Study of Atherosclerosis (MESA). MESA is a US cohort including 6,759 White (38.6%), Chinese (11.9%), Black (27.6%), and Hispanic (22%) men and women initially aged 45-84 years and free of CVD. Participants were contacted at least annually to ascertain clinical events. Incident CVD (MI, Stroke, PAD, CV Death) and ChrIRD death/hospitalization risk per-quartile of lipoprotein marker levels were evaluated using disease-specific multivariable Cox regression models adjusted for traditional risk factors. Results: Disparate risk associations with ChrIRD and CVD were observed (Figure). Elevated small HDLp, total LDLp, and small TRLp, and were inversely associated with ChrIRD events. Additionally, larger TRLp size was associated higher ChrIRD risk. Metrics of HDL, LDL, and TRL associations with incident CVD as expected. In contrast, Very large TRLp was inverse with both clinical outcomes (HR [95% CI] CVD: 0.83 [0.75-0.96] ptrend=0.09, ChrIRD: 0.85 [0.69-0.99], ptrend =0.02). Conclusions: TRL, LDL, and HDL particles differentially associate with CVD and ChrIRD. Established predictors of CVD, including total TRL and LDL particles, small LDL, and large /medium TRL, may be inert or even protective in development of ChrIRD events due to distinct pathophysiologic contributions that warrant further investigation.

Abstract 15399: Proteomic Landscape of Plasma Lipoprotein Responses to Regular Exercise

Introduction: Lipoproteins are among the strongest predictors of CVD and are altered through regular exercise. However, the molecular changes underlying the potential benefits of exercise on plasma lipoproteins are unclear. Methods: Proteins (n=4979) were quantified from the plasma of 647 Black and White adults (56% women, mean age = 34.9 yrs) before and after 20-weeks of endurance exercise training using SomaScan. All subjects had complete data for 7 lipoprotein traits that improved with training: HDL-C, TG, large TG rich lipoprotein particles (LTRLP), small LDL particles (SLDLP), large HDL particles (LHDLP), TRLP size, and LDLP size. Fully adjusted linear mixed models were used to test the association of 1) baseline proteins with baseline lipoproteins and 2) delta proteins with delta lipoproteins (delta = post training - baseline value). Significance was determined as FDR&lt;0.05. Results: We identified numerous proteins associated with baseline levels of at least one of the seven lipoprotein traits (range: 48-1099) and whose changes in response to regular exercise were associated with concomitant changes in lipoproteins (range: 4-95) ( Table 1 ). Substantial overlap was found between proteins associated with lipoproteins across timepoints, with 16 proteins associated with 4 or more lipoprotein traits at both timepoints. Plasma abundance of 12/16 proteins significantly changed with training (FDR &lt;0.05). Additionally, for these proteins plasma abundance changed in concordance with the beneficial direction of the associated lipoprotein trait (e.g., proteins associated with atheroprotective lipoprotein traits increased with training and proteins associated with atherogenic traits decreased). Conclusions: Beneficial alterations to plasma lipoproteins with regular exercise are reflected in changes to the plasma proteome. Proteins identified here may represent novel markers of the benefits of regular exercise and of systemic lipoprotein metabolism.

Sugar-Sweetened Beverage Consumption and Plasma Lipoprotein Cholesterol, Apolipoprotein, and Lipoprotein Particle Size Concentrations in US Adults

Prospective cohort studies have found a relation between sugar-sweetened beverage (SSB) consumption (sodas and fruit drinks) and dyslipidemia. There is limited evidence linking SSB consumption to emerging features of dyslipidemia, which can be characterized by variation in lipoprotein particle size, remnant-like particle (RLP), and apolipoprotein concentrations. To examine the association between SSB consumption and plasma lipoprotein cholesterol, apolipoprotein, and lipoprotein particle size concentrations among US adults. We examined participants from the Framingham Offspring Study (FOS; 1987-1995, n = 3047) and the Women's Health Study (1992, n = 26,218). Concentrations of plasma LDL cholesterol, apolipoprotein B (apoB), HDL cholesterol, apolipoprotein A1 (apoA1), triglyceride (TG), and non-HDL cholesterol, as well as total cholesterol:HDL cholesterol ratio and apoB:apoA1 ratio, were quantified in both cohorts; concentrations of apolipoprotein E, apolipoprotein C3, RLP-TG, and RLP cholesterol (RLP-C) were measured in the FOS only. Lipoprotein particle sizes were calculated from nuclear magnetic resonance signals for lipoprotein particle subclass concentrations (TG-rich lipoprotein particles [TRL-Ps]: very large, large, medium, small, and very small; LDL particles [LDL-Ps]: large, medium, and small; HDL particles [HDL-Ps]: large, medium, and small). SSB consumption was estimated from food frequency questionnaire data. We examined the associations between SSB consumption and all lipoprotein and apoprotein measures in linear regression models, adjusting for confounding factors such as lifestyle, diet, and traditional lipoprotein risk factors. SSB consumption was positively associated with LDL cholesterol, apoB, TG, RLP-TG, RLP-C, and non-HDL cholesterol concentrations and total cholesterol:HDL cholesterol and apoB:apoA1 ratios; and negatively associated with HDL cholesterol and apoA1 concentrations (P-trend range: <0.0001 to 0.008). After adjustment for traditional lipoprotein risk factors, SSB consumers had smaller LDL-P and HDL-P sizes; lower concentrations of large LDL-Ps and medium HDL-Ps; and higher concentrations of small LDL-Ps, small HDL-Ps, and large TRL-Ps (P-trend range: <0.0001 to 0.001). Higher SSB consumption was associated with multiple emerging features of dyslipidemia that have been linked to higher cardiometabolic risk in US adults.

EXERCISE TRAINING-INDUCED CHANGES IN LIPID TRAITS ARE ASSOCIATED WITH CHANGES IN CIRCULATING PROTEINS AND METABOLITES

PURPOSE: To examine the molecular mechanisms underlying beneficial effects of regular exercise on lipid metabolism. METHODS: Circulating proteins (n = 4979), metabolites (n = 300), and lipids/lipoproteins were measured in 647 Black and White adults from the HERITAGE Family Study at baseline and after 20 weeks of supervised endurance training. The current analysis focused on 7 lipid/lipoprotein traits that significantly changed with training: HDL- cholesterol (HDL-C), triglycerides (TG), large TG-rich lipoprotein particles (LTRLP), large HDL particles (LHDLP), small LDL particles (SLDLP), and mean TRLP (TRLPz) and LDLP size (LDLPz). The relationship between exercise-induced fold changes in circulating molecules and changes in lipid traits was examined using sparse canonical correlation analysis, which tests the joint associations between two sets of variables by creating composite canonical variates. All variables were corrected for age, sex, race, BMI, baseline value, and family membership via linear mixed models. RESULTS: We identified 3 canonical variate pairs of exercise-induced changes in lipid traits and circulating molecules. Molecular variate 1 was positively correlated with changes in TG, LTRLP, SLDLP, and TRLPz (r = 0.29-0.57, p < 0.0001). Conversely, molecular variate 3 was negatively correlated with changes in TG, LTRLP, SLDLP, and TRLPz (r = -0.30 to -0.39, p < 0.0001), and positively correlated with changes in LDLPz (r = 0.38, p < 0.0001). Molecular variate 2 was negatively correlated with HDL-C (r = -0.46, p < 0.0001) and LHDLP (r = -0.22, p < 0.0001) changes with training. Molecular loadings on the respective variates were largely distinct (Table 1). CONCLUSIONS: We identified groups of circulating molecules whose changes in response to exercise training are associated with changes in the plasma lipid and lipoprotein profile and may provide insights into the mechanisms underlying exercise-induced changes in lipid metabolism.

Understanding the comorbidity between posttraumatic stress severity and coronary artery disease using genome-wide information and electronic health records.

The association between coronary artery disease (CAD) and posttraumatic stress disorder (PTSD) contributes to the high morbidity and mortality observed for these conditions. To understand the dynamics underlying PTSD-CAD comorbidity, we investigated large-scale genome-wide association (GWA) statistics from the Million Veteran Program (MVP), the UK Biobank (UKB), the Psychiatric Genomics Consortium, and the CARDIoGRAMplusC4D Consortium. We observed a genetic correlation of CAD with PTSD case-control and quantitative outcomes, ranging from 0.18 to 0.32. To investigate possible cause-effect relationships underlying these genetic correlations, we performed a two-sample Mendelian randomization (MR) analysis, observing a significant bidirectional relationship between CAD and PTSD symptom severity. Genetically-determined PCL-17 (PTSD 17-item Checklist) total score was associated with increased CAD risk (odds ratio = 1.04; 95% confidence interval, 95% CI = 1.01-1.06). Conversely, CAD genetic liability was associated with reduced PCL-17 total score (beta = -0.42; 95% CI = -0.04 to -0.81). Because of these opposite-direction associations, we conducted a pleiotropic meta-analysis to investigate loci with concordant vs. discordant effects on PCL-17 and CAD, observing that concordant-effect loci were enriched for molecular pathways related to platelet amyloid precursor protein (beta = 1.53, p = 2.97 × 10-7) and astrocyte activation regulation (beta = 1.51, p = 2.48 × 10-6) while discordant-effect loci were enriched for biological processes related to lipid metabolism (e.g., triglyceride-rich lipoprotein particle clearance, beta = 2.32, p = 1.61 × 10-10). To follow up these results, we leveraged MVP and UKB electronic health records (EHR) to assess longitudinal changes in the association between CAD and posttraumatic stress severity. This EHR-based analysis highlighted that earlier CAD diagnosis is associated with increased PCL-total score later in life, while lower PCL total score was associated with increased risk of a later CAD diagnosis (Mann-Kendall trend test: MVP tau = 0.932, p < 2 × 10-16; UKB tau = 0.376, p = 0.005). In conclusion, both our genetically-informed analyses and our EHR-based follow-up investigation highlighted a bidirectional relationship between PTSD and CAD where multiple pleiotropic mechanisms are likely to be involved.

Sleep and Late-Onset Alzheimer's Disease: Shared Genetic Risk Factors, Drug Targets, Molecular Mechanisms, and Causal Effects.

Late-onset Alzheimer’s disease (AD) is associated with sleep-related phenotypes (SRPs). The fact that whether they share a common genetic etiology remains largely unknown. We explored the shared genetics and causality between AD and SRPs by using high-definition likelihood (HDL), cross-phenotype association study (CPASSOC), transcriptome-wide association study (TWAS), and bidirectional Mendelian randomization (MR) in summary-level data for AD (N = 455,258) and summary-level data for seven SRPs (sample size ranges from 359,916 to 1,331,010). AD shared a strong genetic basis with insomnia (r g = 0.20; p = 9.70 × 10–5), snoring (r g = 0.13; p = 2.45 × 10–3), and sleep duration (r g = −0.11; p = 1.18 × 10–3). The CPASSOC identifies 31 independent loci shared between AD and SRPs, including four novel shared loci. Functional analysis and the TWAS showed shared genes were enriched in liver, brain, breast, and heart tissues and highlighted the regulatory roles of immunological disorders, very-low-density lipoprotein particle clearance, triglyceride-rich lipoprotein particle clearance, chylomicron remnant clearance, and positive regulation of T-cell–mediated cytotoxicity pathways. Protein–protein interaction analysis identified three potential drug target genes (APOE, MARK4, and HLA-DRA) that interacted with known FDA-approved drug target genes. The CPASSOC and TWAS demonstrated three regions 11p11.2, 6p22.3, and 16p11.2 may account for the shared basis between AD and sleep duration or snoring. MR showed insomnia had a causal effect on AD (ORIVW = 1.02, P IVW = 6.7 × 10–6), and multivariate MR suggested a potential role of sleep duration and major depression in this association. Our findings provide strong evidence of shared genetics and causation between AD and sleep abnormalities and advance our understanding of the genetic overlap between them. Identifying shared drug targets and molecular pathways can be beneficial for treating AD and sleep disorders more efficiently.

Abstract P206: Proteomic And Metabolomic Signatures Of Plasma Triglyceride-related Trait Responses To Regular Exercise

Introduction: Elevated plasma triglycerides (TG) are associated with risk of cardiovascular disease and are modifiable through lifestyle interventions such as regular exercise. However, TG responses to regular exercise are characterized by significant inter-individual differences. Hypothesis: We hypothesized that baseline levels of circulating proteins and metabolites are associated with TG response to exercise and can predict exercise-induced changes in plasma TG traits. Methods: We measured circulating proteins (n=4979 proteins) and metabolites (n=300) in 650 Black and White adults of the HERITAGE Family Study who completed 20 weeks of exercise training and had complete data on TG traits. We investigated two TG-related traits that significantly improved with training: fasting TG and large TG-rich lipoprotein particle concentration (LTRLP). The association between baseline analyte values and exercise-induced changes in TG traits were examined using linear mixed models adjusted for age, sex, race, BMI, baseline trait value, and the random effect of family membership. Significance was determined as FDR&lt;0.05. Molecular signatures of TG trait responses were generated via elastic net regression tuned using leave-one-out cross validation. Results: Regular exercise significantly reduced plasma TG (-1.03±1.3 mmol/L, p=0.01) and LTRLP (-0.24±2.2 nmol/L, p= 0.007), with their training-induced changes moderately correlated (r=0.4, p&lt;0.0001). We identified largely distinct panels of baseline analytes associated with changes in TG and LTRLP ( Table 1 ). Similarly, elastic net regression yielded distinct models of 99 analytes for TG and 315 analytes for LTRLP responses to exercise with accuracy of RMSE=1.28 mmol/L for TG and 2.16 nmol/L for the LTRLP model. Conclusions: We identified panels of proteins and metabolites associated with exercise-induced changes in TG traits and demonstrate, within our data, circulating analytes hold promise for predicting the exercise responsiveness of plasma TG-related traits.

Triglyceride-Rich Lipoproteins and Glycoprotein A and B Assessed by 1H-NMR in Metabolic-Associated Fatty Liver Disease.

High plasma triglyceride (TG) levels and chronic inflammation are important factors related to metabolic-associated fatty liver disease in patients at cardiovascular risk. Using nuclear magnetic resonance (1H-NMR), we aimed to study the triglyceride-rich lipoprotein (TRL) and acute-phase glycoprotein profiles of a cohort of patients with metabolic disease and their relationship with fatty liver. Plasma samples of 280 patients (type 2 diabetes, 81.1%; obesity, 63.3%; and metabolic syndrome, 91.8%) from the University Hospital Lipid Unit were collected for the measurement of small, medium and large TRL particle numbers and sizes and glycoprotein profiles (Glyc-A and Glyc-B) by 1H-NMR. Liver function parameters, including the fatty liver index (FLI) and fibrosis-4 (FIB-4) score, were assessed. Hepatic echography assessment was performed in 100 patients, and they were followed up for 10 years. TRL particle concentrations showed a strong positive association with Glyc-A and Glyc-B (ρ=0.895 and ρ=0.654, p<0.001, respectively) and with the liver function-related proteins ALT ρ=0.293, p<0.001), AST (ρ=0.318, p<0.001) and GGT (ρ=0.284, p<0.001). Likewise, TRL concentrations showed a positive association with FLI (ρ=0.425, p<0.001) but not with FIB-4. During the follow-up period of 10 years, 18 new cases of steatosis were observed among 64 patients who were disease-free at baseline. Baseline TRL particle numbers and glycoprotein levels were associated with the new development of metabolic-associated fatty liver disease (MAFLD) (AUC=0.692, p=0.018 and AUC=0.669, p=0.037, respectively). Overall, our results indicated that TRL number and acute-phase glycoproteins measured by 1H-NMR could be potential biomarkers of the development of hepatic steatosis in patients at metabolic risk.

Effects of a low-carbohydrate diet on insulin-resistant dyslipoproteinemia—a randomized controlled feeding trial

ABSTRACTBackgroundCarbohydrate restriction shows promise for diabetes, but concerns regarding high saturated fat content of low-carbohydrate diets limit widespread adoption.ObjectivesThis preplanned ancillary study aimed to determine how diets varying widely in carbohydrate and saturated fat affect cardiovascular disease (CVD) risk factors during weight-loss maintenance.MethodsAfter 10–14% weight loss on a run-in diet, 164 participants (70% female; BMI = 32.4 ± 4.8 kg/m2) were randomly assigned to 3 weight-loss maintenance diets for 20 wk. The prepared diets contained 20% protein and differed 3-fold in carbohydrate (Carb) and saturated fat as a proportion of energy (Low-Carb: 20% carbohydrate, 21% saturated fat; Moderate-Carb: 40%, 14%; High-Carb: 60%, 7%). Fasting plasma samples were collected prerandomization and at 20 wk. Lipoprotein insulin resistance (LPIR) score was calculated from triglyceride-rich, high-density, and low-density lipoprotein particle (TRL-P, HDL-P, LDL-P) sizes and subfraction concentrations (large/very large TRL-P, large HDL-P, small LDL-P). Other outcomes included lipoprotein(a), triglycerides, HDL cholesterol, LDL cholesterol, adiponectin, and inflammatory markers. Repeated measures ANOVA was used for intention-to-treat analysis.ResultsRetention was 90%. Mean change in LPIR (scale 0–100) differed by diet in a dose-dependent fashion: Low-Carb (–5.3; 95% CI: –9.2, –1.5), Moderate-Carb (–0.02; 95% CI: –4.1, 4.1), High-Carb (3.6; 95% CI: –0.6, 7.7), P = 0.009. Low-Carb also favorably affected lipoprotein(a) [–14.7% (95% CI: –19.5, –9.5), –2.1 (95% CI: –8.2, 4.3), and 0.2 (95% CI: –6.0, 6.8), respectively; P = 0.0005], triglycerides, HDL cholesterol, large/very large TRL-P, large HDL-P, and adiponectin. LDL cholesterol, LDL-P, and inflammatory markers did not differ by diet.ConclusionsA low-carbohydrate diet, high in saturated fat, improved insulin-resistant dyslipoproteinemia and lipoprotein(a), without adverse effect on LDL cholesterol. Carbohydrate restriction might lower CVD risk independently of body weight, a possibility that warrants study in major multicentered trials powered on hard outcomes. The registry is available through ClinicialTrials.gov: https://clinicaltrials.gov/ct2/show/NCT02068885.

The NIH Lipo-COVID Study: A Pilot NMR Investigation of Lipoprotein Subfractions and Other Metabolites in Patients with Severe COVID-19.

A complex interplay exists between plasma lipoproteins and inflammation, as evidenced from studies on atherosclerosis. Alterations in plasma lipoprotein levels in the context of infectious diseases, particularly respiratory viral infections, such as SARS-CoV-2, have become of great interest in recent years, due to their potential utility as prognostic markers. Patients with severe COVID-19 have been reported to have low levels of total cholesterol, HDL-cholesterol, and LDL-cholesterol, but elevated levels of triglycerides. However, a detailed characterization of the particle counts and sizes of the different plasma lipoproteins in patients with COVID-19 has yet to be reported. In this pilot study, NMR spectroscopy was used to characterize lipoprotein particle numbers and sizes, and various metabolites, in 32 patients with severe COVID-19 admitted to the intensive care unit. Our study revealed markedly reduced HDL particle (HDL-P) numbers at presentation, especially low numbers of small HDL-P (S-HDL-P), and high counts of triglyceride-rich lipoprotein particle (TRL-P), particularly the very small and small TRL subfractions. Moreover, patients with severe COVID-19 were found to have remarkably elevated GlycA levels, and elevated levels of branched-chain amino acids and beta-hydroxybutyrate. Finally, we detected elevated levels of lipoproteins X and Z in most participants, which are distinct markers of hepatic dysfunction, and that was a novel finding.

Role of growth hormone in hepatic and intestinal triglyceride-rich lipoprotein metabolism

Elevated plasma concentrations of hepatic- and intestinally-derived triglyceride-rich lipoproteins (TRL) are implicated in the pathogenesis of atherosclerotic cardiovascular disease and all-cause mortality. Excess of TRL is the driving cause of atherogenic dyslipidemia commonly occurring in insulin-resistant individuals such as patients with obesity, type 2 diabetes and metabolic syndrome. Interestingly, growth hormone (GH)-deficient individuals display similar atherogenic dyslipidemia, suggesting an important role of GH and GH deficiency in the regulation of TRL metabolism. We aimed to examine the direct and/or indirect role of GH on TRL metabolism. We investigated the effect on fasting and postprandial hepatic-TRL and intestinal-TRL metabolism of short-term (one month) withdrawal of GH in 10 GH-deficient adults. After GH withdrawal, we found a reduction in fasting plasma TRL concentration (significant decrease in TRL-TG, TRL-cholesterol, TRL-apoB-100, TRL-apoC-III and TRL-apoC-II) but not in postprandial TRL response. This reduction was due to fewer fasting TRL particles without a change in TG per particle and was not accompanied by a change in postprandial TRL-apoB-48 response. Individual reductions in TRL correlated strongly with increases in insulin sensitivity and decreases in TRL-apoC-III. In this relatively short term 'loss of function' human experimental model, we have shown an unanticipated reduction of hepatic-TRL particles despite increase in total body fat mass and reduction in lean mass. These findings contrast with the atherogenic dyslipidemia previously described in chronic GH deficient states, providing a new perspective for the role of GH in lipoprotein metabolism.

Triglyceride-rich lipoprotein and LDL particle subfractions and their association with incident type 2 diabetes: the PREVEND study

BackgroundTriglyceride-rich lipoproteins particles (TRLP) and low density lipoprotein particles (LDLP) vary in size. Their association with β-cell function is not well described. We determined associations of TRLP and LDLP subfractions with β-cell function, estimated as HOMA-β, and evaluated their associations with incident T2D in the general population.MethodsWe included 4818 subjects of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study without T2D at baseline. TRLP and LDLP subfraction concentrations and their average sizes were measured using the LP4 algorithm of the Vantera nuclear magnetic resonance platform. HOMA-IR was used as measure of insulin resistance. HOMA-β was used as a proxy of β-cell function.ResultsIn subjects without T2D at baseline, very large TRLP, and LDL size were inversely associated with HOMA-β, whereas large TRLP were positively associated with HOMA-β when taking account of HOMA-IR. During a median follow-up of 7.3 years, 263 participants developed T2D. In multivariable-adjusted Cox regression models, higher concentrations of total, very large, large, and very small TRLP (reflecting remnants lipoproteins) and greater TRL size were associated with an increased T2D risk after adjustment for relevant covariates, including age, sex, BMI, HDL-C, HOMA-β, and HOMA-IR. On the contrary, higher concentrations of large LDLP and greater LDL size were associated with a lower risk of developing T2D.ConclusionsSpecific TRL and LDL particle characteristics are associated with β-cell function taking account of HOMA-IR. Moreover, TRL and LDL particle characteristics are differently associated with incident T2D, even when taking account of HOMA-β and HOMA-IR.